This proposal seeks to re-establish a Comprehensive Sickle Cell Center at the University of Southern California School of Medicine and its associated institutions. The focus of the research effort at this Center has been directed at the pathophysiology, clinical consequences and treatment of vascular occlusion in Sickle Cell Anemia and its variants. Vascular occlusion represents the most important cause of morbidity and mortality in this disease, yet its pathophysiology is still incompletely understood, and its treatment remains unsatisfactory. The present proposal centers its effort on our hypothesis that poorly deformable dense erythrocytes, abnormally adherent erythrocytes and poorly deformable neutrophils combine to initiate the cascade of events that ultimately lead to recurrent vascular obstruction, ischemia and infarction in this disease. The specific aims of the proposal are: i) to develop an improved understanding of the pathophysiology of vascular occlusion in sickle cell disease and ii) to develop improved methods of preventing vascular occlusion in this disease. Project 1 seeks to further define the relationships between globin gene haplotypes and disease expression. Project 2 focuses on the molecular and biochemical mechanisms of RBC adherence to endothelium. Project 3 will study neutrophil physiology in this disease and its role in vaso-occlusion. Project 4 seeks to determine the effect of specific therapeutic maneuvers on the clinical course of cerebrovascular disease. Project 5 employs a novel strategy to define the beneficial effect of hydroxyurea in retarding the clinical progression of certain complications of the disease associated with poor prognosis. These 5 research projects are supported by 3 cores: data coordinating, adhesion laboratory, and hemorheology laboratory, which function to promote the overall research effort. This application has been developed to promote collaboration within our Center and, through projects 4 and 5, seeks collaboration with other Centers and supports the goals of the National Sickle Cell Disease Program.